4,5-Dihydro-isoxazole derivatives and their pharmaceutical use

A compound of formula

• 183
• wherein m, n and p are each independently 0 or 1 and q is 0, 1, 2, 3, 4 or 5;
• * indicates an asymmetric carbon atom which can be R or S;
• -A1=A2-A3=A4- is a bivalent radical of formula
• —N═CH—CH═CH— (a-1) —CH═N—CH═CH— (a-2) —CH═CH—CH═N— (a-3) —CH═CH—N═N— (a4) —N═CH—N═CH— (a-5) —N═CH—CH═N— (a-6) —CH═CH—CH═CH— (a-7);
• B is a bivalent radical of formula
• 184
• D is Ar1 or Het1;
• Q is a direct covalent bond or a bivalent radical of formula
• 185 186
• ;
• wherein X1 and X2 are each independently S or O, t is 0, 1 or 2;
• X3 is independently S, O or NR26;
• X4 an X5 are each idependently N or CH.
• L is Ar1 or Het1;
• R1 is selected from hydrogen, halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(3-6)cycloalkylC(1-6)alkyl, C(3-6)cycloalkyloxy, haloC(1-6)alkyl, cyano, guanidine, nitro and NR17R18;
• R2 and R3 are each independently selected from hydrogen, halo, C(1-6)alkyloxy and C(1-6)alkyl where the alkyl moiety may be optionally substituted by one or more hydroxy [for example 1, 2 or 3];
• R4 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl and
• C(3-6)cycloalkenyl;
• R5, R6, R9 and R10 are each independently selected from hydrogen, hydroxy, halo, C(1-6)alkyl, [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR17R18, (SO2)R16, (C═O)R16, Ar1 and Het1], C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, (═O), NR17R18, (SO2)R16, (C═O)R16, Ar1 and Het1], cyano, (C═O)R25, (C═O)OR16, (SO2)R16, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1;
• or
• R5 and R6 or R9 and R10 together with the carbon atom to which they are attached, form a Het1 or a C(2-14) carbocyclic radical optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (C═O)R22, C(6-14)aryl and C(1-4)heterocycle], cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C(1-14)heterocycle;
• R7 and R8 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl,
• C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, hydroxyC(1-6)alkyl and C(1-6)alkyloxy;
• R11 is selected from hydrogen, hydroxy and C(1-6)alkyloxy [where the alkyloxy moiety may be optionally substituted by (C═O)R6];
• R12 is selected from hydrogen and hydroxy;
• R13 is selected from hydrogen, hydroxy, halo, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, (═O), NR17R18, (SO2)R16, (C═O)R17, Ar1 and Het1, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1;
• R14 and R15 are each independently selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(3-6)cycloalkyl,
• C(1-6)alkyloxy, cyano, (C═O)R16, Ar1 and Het1], C(6-14)arylC(1-6)alkyl, (C═O)R16, (C═O)OR16, (C═S)R16, (SO2)R16, Ar1 and Het1;
• or
• R14 and R15 together with the N atom to which they are attached, form a C(1-14)heterocycle optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl and
• C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxy, (C═O)R16, Ar1 and Het1], C(6-14)arylthio, C(6-14)aryloxy, cyano, (C═O)R16, (C═O)OR16, (SO2)R16, NR17R18, Ar1 and Het1;
• R16 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl,
• C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxycarbonyl, NR17R18, Ar1 and Het1], NR17R18, C(6-14)aryloxy, Ar1 or Het1;
• R17 and R18 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(3-6)cycloalkyl,
• C(1-6)alkyloxy, (C═O)R19, Ar1 and Het1], (C═O)R19, (SO2)R19, Ar1 and Het1;
• or
• R17 and R18 together with the N atom to which they are attached, form a C(1-14)-heterocycle optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy,
• C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(1-6)alkyloxy, (C═O)R19, Ar1 and Het1], NR20R21, (C═O)R19, (═NH), S—Ar1, Ar1 and Het1;
• R19 is selected from C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl,
• C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, (C═O)R22, NR20(R21, Ar1 and Het1], phenyloxy, NR20R21, Ar1 and Het1;
• R20 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, NH(C═O)R22 and C(1-6)alkyloxy;
• R21 is selected from hydrogen, hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(1-6)alkyloxycarbonyl, Ar and Het1;
• Ar1 is a C(6-14)aryl (or C(6-14)arylidene when D is Ar1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl,
• C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (C═O)R22, C(6-14)aryl and C(1-14)heterocycle], cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C(1-14)heterocycle;
• Het1 is a C(1-14)heterocycle (or C(1-4)heterocyclidene when D is Het1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl,
• C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo,
• C(1-)alkyloxy, NR23R24, (C═O)R22,C(6-14)aryl and C(1-14)heterocycle], cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R23R24C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C(1-14)heterocycle;
• R22 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(1-6)alkyloxy, haloC(1-6)alkyl, NR23R24 and
• 187
• R23 and R24 are each independently selected from hydrogen, C(1-6)alkyl and
• 188
• R25 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl,
• C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxycarbonyl, NR17R18, Ar1 and Het1], C(6-14)aryloxy, Ar1 and Het1;
• R26 is selected from hydrogen, C(1-6)alkyl and phenyl;
• or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof.